Assistant Professor (also Medicine)
6206B Biochemical Sciences Building
440 Henry Mall, Madison, WI 53706
• B.S., M.Sc., Istanbul University, School of Pharmacy, 2001
• Ph.D., Baylor College of Medicine, 2007
• Postdoctoral Fellow, Harvard University, 2013
Honors & Awards
• Translational Basic & Clinical Pilot Award, Institute for Clinical and Translational Research, 2018
• Shaw Scientist Award, Greater Milwaukee Foundation, 2016
• Career Development Award, Juvenile Diabetes Research Foundation, 2014
• Research Scientist Development Award (KO1), National Institute of Health, 2014
• Young Investigator Award, American Society of Bone and Mineral Research, 2007
The endoplasmic reticulum (ER) is a dynamic organelle that plays a key role for cellular homeostasis, development, and stress responsiveness. In response to cellular stress induced by toxins, unfolded proteins and inflammation, a well-established signaling cascade, the unfolded protein response (UPR), is activated. During UPR, perturbations in ER homeostasis are sensed and transduced by ER membrane localized proteins to the cytoplasm and nucleus to initiate a compensatory response. While UPR plays a critical role for cell survival during acute stress conditions, hyperactivated UPR or unresolvable stress lead to cell demise. Thus, the unfolded protein response regulates both death and survival effectors. How or when these ER membrane proteins determine whether a cell will survive or die upon ER stress is currently unknown.
We recently showed that, the adaptive functions of the UPR were greatly reduced in β-cells of two different type 1 diabetes (T1D) mouse models and human patients during the progression of T1D. Diabetes incidence in these mouse models was dramatically reduced by mitigating β-cell ER stress with a chemical chaperone. These data suggest that the UPR plays a critical role in β-cell function and survival in T1D. Although this study provides the first direct link between the UPR and T1D pathogenesis and opens the door to a completely novel area of T1D biology, the β-cell specific function of the UPR sensors, their downstream targets, and the molecular mechanisms by which the UPR regulates pancreatic β-cell death/survival during T1D progression still remain largely unknown.
Our laboratory uses biochemistry, cell biology, genetics, -omics and immunology as well as sophisticated genetic and pharmacological tools to understand β-cell specific functions of the UPR sensors, their downstream targets and the molecular mechanisms by which the UPR regulates pancreatic β-cell death/survival.
Publications of Note
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• Uncoupling of Metabolic Health from Longevity through Genetic Aleration of Adipose Tissue Lipid-Binding Proteins.
Charles KN, Li MD, Engin F, Arruda AP, Inouye K, Hotamisligil GS.
Cell Rep. 2017 Oct 10;21(2):393-402.
• The Inhibitory G Protein α-Subunit, Gαz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice. Fenske RJ, Cadena MT, Harenda QE, Wienkes HN, Carbajal K, Schaid MD, Laundre E, Brill AL, Truchan NA, Brar H, Wisinski J, Graham TE, Engin F, Kimple ME. Endocrinology 2017 June 1
• Engin F. ER Stress and Development of Type 1 Diabetes. J Investig Med. 2015 Jul 30 [Epub ahead of print]
• Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms.
Brozzi F, Nardelli TR, Lopes M, Millard I, Barthson J, Igoillo-Esteve M, Grieco FA, Villate O, Oliveira JM, Casimir M, Bugliani M, Engin F, Hotamisligil GS, Marchetti P, Eizirik DL. Diabetologia. 2015 Jun 23. [Epub ahead of print]
• Engin F, Nguyen T, Yermalovich A, Hotamisligil GS. (2014) Aberrant islet unfolded protein response in type 2 diabetes. Sci Rep 4:4054
• Engin F, Yermalovich A, Nguyen T, Nguyen T, Hummasti S, Fu W, Eizirik DL, Mathis D, Hotamisligil GS. (2013) Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes. Sci Transl Med 5(211)
• Engin, F., Hotamisligil, GS. (2010) Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes. Metab. 12(Supplement):108-115
• Yang, T., Londono, R.M., Lu, H., Li, K., Keller, B., Jiang, M.M., Chen, Y., Bertin, T., Engin, F., Dabovic, B., Rifkin, D.B., Hicks, J, Beaudet, A.L., Lee, B. (2010) E-Selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β. J. Clin. Invest. 120(7):2474–2485
• Engin, F., Lee B. (2010) NOTCHing the bone: insights into multi-functionality. Bone 46(2):274-280
• Engin, F., Bertin, T., Ma, O., Jiang, MM., Wang, L., Sutton, RE., Donehower, LA., Lee, B. (2009) Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum. Mol. Genet 18(8):1464-1470
• Engin, F., Yao, Z., Yang, T., Zhou, G., Bertin, T., Jiang, M.M., Chen, Y., Wang, L., Zheng, L., Sutton, R.E., Boyce, B.F., Lee, B. (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat. Med. 14(3):299-305
• Zhou, G., Zheng, Q., Engin, F., Munivez, E., Chen, Y., Sebald, E., Krakow, D., Lee, B. (2006) Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc. Natl. Acad. Sci. 103(50):19004-9